title: Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse.
abstract: Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cheng
authors.forename: Aiping
authors.initials: A
authors.lastname: Bai
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Beckham
authors.forename: S Tucker
authors.initials: ST
authors.lastname: Marrison
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Yount
authors.forename: Katherine
authors.initials: K
authors.lastname: Young
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bartlett
authors.forename: Bill X
authors.initials: BX
authors.lastname: Wu
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Keane
authors.forename: Kent E
authors.initials: KE
authors.lastname: Armeson
authors.forename: David T
authors.initials: DT
authors.lastname: Marshall
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Keane
authors.forename: Michael T
authors.initials: MT
authors.lastname: Smith
authors.forename: E Ellen
authors.initials: EE
authors.lastname: Jones
authors.forename: Richard R
authors.initials: RR
authors.lastname: Drake
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.forename: James S
authors.initials: JS
authors.lastname: Norris
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004790:Enzyme Induction / Q000528:radiation effects; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000517:prevention & control; D011401:Promoter Regions, Genetic; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013107:Sphingolipids / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; C421619:N-(1-(4-nitrophenyl)-1,3-dihydroxyprop-2-yl)tetradecanamide; D011412:Propanolamines; D016755:Proto-Oncogene Proteins c-jun; D011838:Radiation-Sensitizing Agents; D013107:Sphingolipids; D018808:Transcription Factor AP-1; C526693:ASAH1 protein, human; D055573:Acid Ceramidase